The present invention relates to a method for the treatment of alcohol and drug dependence.
More specifically the present invention relates to a method for the treatment of the alcohol dependence.
It relates also to a method for the treatment of a dependence to drugs such as opioid derivatives, cannabinoides, nicotin derivatives, amphetamines and tranquilizers.
The present invention also relates to compositions and kits for such treatment.
A number of studies indicated a relationship between alcohol intake and endogenous opioid activity (Schulz R., Wuster M., Duka T., Herz A., Acute and chronic ethanol treatment changes endorphin levels in brain and pituitary, Psychopharmacology, 68, 221-227, 1980; Hoffman P., Melchior C., Ritzmann R. F., Tabakoff B., Structural requirements for neurohypophyseal peptide effects of ethanol tolerance, Alcohol Exp. Clin. Res., 5, 154, 1981). Ethanol intake increases synthesis and release of beta endorphin in the pituitary gland and the stimulation of opiate receptors seems to be weakly involved in the regulation of positive reinforcement properties of ethanol. These findings have suggested the use of opiates antagonists (such as naloxone or naltrexone) to prevent ethanol-induced analgesia, intoxication, coma (Kiianmaa K., Tabakoff B. Neurochemical correlates of tolerance and strain differences in the neurochemical effects of ethanol, Pharm. Biochem. Behav., 18, 383-388, 1983) or more recently ethanol dependence (Davidson D., Amit Z., Naltrexone blocks acquisition of voluntray ethanol intake in rats, Alcohol Clin. Exp. Res., 21, 677-683, 1997). Naltrexone, when used together with supportive therapy, has been shown to reduce the rate of relapse to heavy drinking in alcohol dependent patients (O""Malley S. S., Opioid antagonists in the treatment of alcohol dependence: clinical efficacy and prevention of relapse, Alcohol Alcoholism 31, 77-91, 1996).
The present invention provides a method for the treatment of alcohol and drug dependence comprising administering to a patient a therapeutically effective amount of a combination of: (i) an opioid antagonist, such as naltrexone or naloxone; and (ii) a NMDA receptor complex modulator, in particular a spermidine site modulator. The present invention is also directed to compositions and pharmaceutical kits containing the same. Such combination therapy provides surprisingly efficient and effective methodology for use in the treatment of alcohol and drug dependence.
The NMDA subtype of the glutamate receptor is a ligand-gated ion channel involved in excitatory neurotransmission in the mammalian CNS. Activation of the NMDA receptor-channel complex has been implicated in several physiological phenomena important to higher order CNS functions. Overstimulation of this receptor results in an inflow of Ca++ and neuronal excititoxicity. This ligand-gated ionotropic glutamate receptor is subject to complex regulation by a number of ligands. Separate regulatory sites include the binding site for the agonist I-glutamate; a high affinity binding site for the obligatory co-agonist glycine; a site where Zn++ acts to allosterically inhibit the agonist-induced response independently of membrane potential; a site within the channel where Mg++ and phencyclidine (PCP), dizocilpine and ketamine bind to produce a voltage-dependent open channel block; and a distinct binding site for the endogenous polyamines, spermine and spermidine, which modulate NMDA receptor function (Bergeron et al., J. Med. Chem., 39, 5257, 1996).
Spermidine can modulate certain NMDA receptor subtypes by either glycine-independent or glycine dependent mechanisms (or both). This action of polyamines to potentiate agonist-mediated responses may reside in its shielding of the NMDA receptor proton sensor from the extracellular pH. The influence of polyamines in vivo will depend on effective extracellular levels and the presence of suitable polyamine sensitive NMDA receptors sub-units. These in vivo effects of polyamines on NMDA receptor may explain the excessive activation of NMDA receptors observed during some pathological situations in which polyamine synthesis is not preserved.
Acamprosate is an example of a compound which is able to induce a modulation of the NMDA receptor complex by interactions on a spermidine sensitive site.
Other examples of compounds which induce a modulation of the NMDA receptor complex are:
glycine antagonists such as L 701 324 (J. Kotlinska et al., Psychopharmacology, 127, 238, 1886);
ibogaine: (Popick P. et al., J. Pharmacol. Exp. Ther., 275, 753, 1995),
memantine and derivatives: (Popick P. et al., Pharmacol. Biochem. Behav., 53, 791, 1996),
ifenprodil and eliprodil: (Schoemaker II. et al., Eur. J. Pharmacol., 176, 240, 1990),
modulators of the NMDA receptor complex on the glycine site (Bienkowski P., Alcohol, 15, 87, 1998).
By xe2x80x9cadministering a combinationxe2x80x9d, or the like, when referring to component (i), and component (ii), of the present invention, it is meant that the components are administered concurrently to a patient being treated. By concurrently, it is meant that each component may be administered at the same time or sequentially in any order at different points in time. However if not administered at the same time, they should be administered sufficiently closely in time so as to provide the desired treatment effect. Suitable dosing intervals and dosing order with such compounds will be readily apparent to those skilled in the art, once armed with the present disclosure. Preferably, all components are administered at the same time, and if not administered at the same time, preferably they are all administered less than one hour apart from one another.
The present invention also includes pharmaceutical compositions comprising or consisting essentially of, in combination, an opioid antagonist (such as naltrexone), and a NMDA receptor complex modulator. Such compositions may be in solid, liquid, transdermal, transnasal, or depot dosage units and may further include a suitable pharmaceutical carrier. Examples of compositions for the oral route are coated tablets and capsules.
The present invention also includes pharmaceutical kits comprising or consisting essentially of an opioid antagonist (such as naltrexone), together with a NMDA receptor complex modulator. In the kit, the opioid antagonist and the NMDA receptor complex modulator may each be presented in separate vials as compounds, and/or in separate vials as compounds in combination with a pharmaceutically acceptable carrier. Alternatively, the opioid antagonist and the NMDA receptor complex modulator may be combined together in one or more vials, with or without a carrier. Thus, for example, the invention includes pharmaceutical kits comprising a separate vial comprising the opioid antagonist and a separate vial comprising the NMDA receptor complex modulator, each vial also containing, if desired, a carrier.
The compositions and kits of the present invention may be employed in the treatment of alcohol and drug dependence.
For use in the treatment of diseases characterized by abnormally high consumption of alcohol, a daily dosage of active ingredients can be about 0.5 to 20 mg/kg of body weight for the opioid antagonist such as naltrexone and about 10 to 400 mg/kg of body weight for a NMDA receptor complex modulator such as acamprosate.